Contrast agents (CAs) are widely used to enhance magnetic resonance imaging (MRI) contrast. The administration of Extrinsic CAs, such as gadolinium (Gd) containing CAs, are thought to achieve contrast by the paramagnetic relaxation effect of a metal-ion to shorten the bulk water relaxation time via rapid exchange of the metal ion's inner-sphere water molecules with bulk solvent. The ability to turn CAs on or off raises the possibility of using such CAs to measure changes in physiological status of tissue samples. For example some CAs exclude Gd from the inner sphere while inactive, and then on activation expose bulk water to a rapidly exchanging water site on the Gd. However, the utility of such CAs in living subjects may be limited by toxicity and undesirable spin-spin lattice relaxation time (T2*) effects. In addition, CAs having a slow rate of water exchange are disfavored because this hampers the metal-ion's ability to shorten the bulk water relaxation time and thus enhance contrast.
Chemical exchange saturation transfer (CEST) is an alternative technique to enhance MRI contrast. Contrary to the above described CAs, CEST favors CAs having a slow rate of water exchange. For example, intrinsic metabolites with slowly exchangeable NH or OH sites may be saturated to produce a direct intensity decrease in the bulk water signal by Magnetization Transfer (MT). It may also be possible to develop MT-based CA that turn on an off in response to a physiologic parameter, such as pH, if the exchange rate of the NH or OH sites are sensitive to changes in that parameter. However, because the chemical shifts of such diamagnetic NH and OH groups in intrinsic metabolites are typically within 5 ppm of bulk water, it can be difficult to avoid off-resonance saturation of bulk water or tightly protein-bound water in tissue samples. Extrinsic CAs may similarly enhance image contrast by MT. Such CAs, however, rely on the chemical exchange of NH or OH functional groups covalently bonded to the CA and close to the resonance frequency of bulk water.
Accordingly, what is needed is an improved MT-based CA that is amenable to discriminating and reporting on the changing metabolic status of a target sample in contrast to its surroundings.